Mutation of neurotrophic tyrosine receptor kinase can promote pan-cancer immunity and the efficacy of immunotherapy

The Neurotrophic tyrosine receptor kinase (NTRK) family plays important roles in tumor progression and is involved in tumor immunogenicity. Here, we conducted a comprehensive bioinformatic and clinical analysis to investigate the characteristics of NTRK mutations and their association with the outcomes in pan-cancer immunotherapy. In 3888 patients across 12 cancer types, patients with NTRK-mutant tumors showed more benefit from immunotherapy in terms of objective response rate (ORR; 41.7% vs. 27.5%; P < 0.001), progress-free survival (PFS; HR = 0.80; 95% CI, 0.68–0.96; P = 0.01), and overall survival (OS; HR = 0.71; 95% CI, 0.61–0.82; P < 0.001). We further constructed and validated a nomogram to estimate survival probabilities after the initiation of immunotherapy. Multi-omics analysis on intrinsic and extrinsic immune landscapes indicated that NTRK mutation was associated with enhanced tumor immunogenicity, enriched infiltration of immune cells, and improved immune responses. In summary, NTRK mutation may promote cancer immunity and indicate favorable outcomes in immunotherapy. Our results have implications for treatment decision-making and developing immunotherapy for personalized care. Supplementary Information The online version contains supplementary material available at 10.1186/s12943-024-01986-0.

may impact the tumor immunogenicity.Indeed, previous studies revealed that colorectal tumors harboring NTRK fusions defined a unique subtype with high microsatellite instability [4].In lung cancer, NTRK alteration was positively associated high tumor mutation burden (TMB) [5].We speculated the mutation of NTRK could enhance the immune responses and be a potential biomarker in immunotherapy.Therefore, here we conducted a comprehensive bioinformatic and clinical analysis to examine the characteristics of NTRK (NTRK1, NTRK2, and NTRK3) gene mutations and their association with the clinical outcomes of pan-cancer immunotherapy (Suppl.Methods).
The major intrinsic immune response included high tumor immunogenicity, activation of the antigen-processing machinery, and the over-expression of costimulatory molecules [6].As shown in Fig. 2A, NTRK mutation was associated with higher TMB, non-silent mutation rate, and silent mutation rate.Next, we examined if there were any specific mutation patterns which were associated with the efficacy of immunotherapy.The frequencies of all known COSMIC reference signatures in NTRKmutant and NTRK-non-mutant tumors were compared.As shown in Suppl Fig. 6A, the frequencies of SBS7a (known etiology, ultraviolet light exposure), SBS10b (POLE mutation), SBS30 (defective DNA base excision repair), and SBS86 (unknown chemotherapy treatment) changed significantly in NTRK-mutant tumors.Further analysis revealed these four signatures were predictive (See figure on previous page.)Fig. 1 The mutation of NTRK gene family as an independent predictive biomarker in pan-cancer immunotherapy.(A) Kaplan-Meier survival analysis stratified by NTRK mutation status in 1610 cancer patients with 10 types of tumors treated with ICIs in the discovery cohort.(B) Association between NTRK mutation and OS in 2278 patients with 7 types of tumors treated with ICIs in the validation cohort.(C-E) Comparison of OS (C), ORR (D), and PFS (E) between patients with NTRK mutation and patients with NTRK non-mutation in 3888 patients with 12 tumor types treated with ICIs.(F-G) Univariate (F) and multivariate (H) Cox analysis of the association between NTRK mutation and OS in 3888 patients with 12 tumor types treated with ICIs.(H) Nomogram to predict the 12-and 24-month survival.It can calculate overall survival from the date of immunotherapy start.To use, locate 'age' axis and draw a line up to the 'point' axis to get a score associated with age, repeat for the other features to get their scores.Sum all scores and locate it on the 'total point' axis, draw a line to '12-month survival' axis to get the 12-month OS probability.(I-J) Based on the optimal cutoff value derived from nomogram, low-score was associated with favorable OS in both discovery cohort (I) and validation cohort (J).CI, confidence interval; CR, complete response; HR, hazard ratio; ICI, immune checkpoint inhibitor; ORR, objective response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease; TMB, tumor mutation burden biomarkers for OS in patients treated with ICIs (Suppl Fig. 6B).Additionally, the mRNA expression levels of three major immune checkpoints (PD-1, PD-L1, and CTLA-4) were significantly elevated in NTRK-mutant tumors (Fig. 2B).We also observed most of 16 major histocompatibility complex (MHC) and 25 costimulatory molecules were increased in NTRK-mutant tumors (Fig. 2G).
The key extrinsic immune characteristics included the infiltration of immune cells into the tumor microenvironment, high diversity of B cell receptors (BCRs) and T cell receptors (TCRs), activated immunogenicity of cancer cells contribute to the immune response, and high expression level of immune-stimulators and chemokines [7].Compared with NTRK-non-mutant tumors (Fig. 2C), NTRK-mutant tumors exhibited higher levels of immune cell infiltration according to (1) leukocyte fractions measured by DNA methylation arrays; (2) lymphocytes fraction estimated from CIBERSORT algorithm; and (3) genomic evaluation of the tumor-infiltrating lymphocyte (TIL) fraction.The abundances of SNV/Indel neoantigens and the diversity of TCR/BCR were significantly upregulated in NTRK-mutant tumors (Fig. 2D).ssG-SEA could quantify 29 common immune signatures including key immune pathways, cells, and functions in tumor microenvironment (Fig. 2E) [8].The MCP-counter method calculated the abundance of 9 immune and 2 stromal cell populations (Fig. 2F) [9].The immune signatures and cell populations were clearly enriched in NTRK-mutant tumors.Additionally, NTRK-mutant tumors were associated with increased expression of 48 known chemokines and their receptors (Fig. 2H) and 39 immune-stimulators (Fig. 2I).
These results derived from intrinsic and extrinsic immune landscapes indicated that NTRK mutation was associated with enhanced tumor immunogenicity, enriched infiltration of immune cells, and improved immune responses, which might explain that patients with NTRK mutant tumors showed favorable outcomes when treated with ICIs.
In summary, NTRK-mutant tumors might be regarded as immunologically "hot" tumors as they could promote both intrinsic and extrinsic tumor immunogenicity.Moreover, NTRK mutation was an independent biomarker for favorable outcomes in cancer immunotherapy.These results have implications for treatment decisionmaking and developing immunotherapy for personalized care.